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| 2. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 3. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 4. |
- Rao, Mukund P., et al.
(författare)
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A double bootstrap approach to Superposed Epoch Analysis to evaluate response uncertainty
- 2019
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Ingår i: Dendrochronologia. - : Elsevier BV. - 1125-7865 .- 1612-0051. ; 55, s. 119-124
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Tidskriftsartikel (refereegranskat)abstract
- The association between climate variability and episodic events, such as the antecedent moisture conditions prior to wildfire or the cooling following volcanic eruptions, is commonly assessed using Superposed Epoch Analysis (SEA). In SEA the epochal response is typically calculated as the average climate conditions prior to and following all event years or their deviation from climatology. However, the magnitude and significance of the inferred climate association may be sensitive to the selection or omission of individual key years, potentially resulting in a biased assessment of the relationship between these events and climate. Here we describe and test a modified double-bootstrap SEA that generates multiple unique draws of the key years and evaluates the sign, magnitude, and significance of event-climate relationships within a probabilistic framework. This multiple re-sampling helps quantify multiple uncertainties inherent in conventional applications of SEA within dendrochronology and paleoclimatology. We demonstrate our modified SEA by evaluating the volcanic cooling signal in a Northern Hemisphere tree-ring temperature reconstruction and the link between drought and wildfire events in the western United States. Finally, we make our Matlab and R code available to be adapted for future SEA applications.
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| 5. |
- Benjamin, Daniel J., et al.
(författare)
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Redefine statistical significance
- 2018
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 2:1, s. 6-10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Bombarda, F., et al.
(författare)
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Runaway electron beam control
- 2019
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 61:1
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Del Genio, Anthony D., et al.
(författare)
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Climates of Warm Earth-like Planets. III. Fractional Habitability from a Water Cycle Perspective
- 2019
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Ingår i: Astrophysical Journal. - : IOP PUBLISHING LTD. - 0004-637X .- 1538-4357. ; 887:2
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Tidskriftsartikel (refereegranskat)abstract
- The habitable fraction of a planet's surface is important for the detectability of surface biosignatures. The extent and distribution of habitable areas are influenced by external parameters that control the planet's climate, atmospheric circulation, and hydrological cycle. We explore these issues using the ROCKE-3D general circulation model, focusing on terrestrial water fluxes and thus the potential for the existence of complex life on land. Habitability is examined as a function of insolation and planet rotation for an Earth-like world with zero obliquity and eccentricity orbiting the Sun. We assess fractional habitability using an aridity index that measures the net supply of water to the land. Earth-like planets become "superhabitable" (a larger habitable surface area than Earth) as insolation and day-length increase because their climates become more equable, reminiscent of past warm periods on Earth when complex life was abundant and widespread. The most slowly rotating, most highly irradiated planets, though, occupy a hydrological regime unlike any on Earth, with extremely warm, humid conditions at high latitudes but little rain and subsurface water storage. Clouds increasingly obscure the surface as insolation increases, but visibility improves for modest increases in rotation period. Thus, moderately slowly rotating rocky planets with insolation near or somewhat greater than modern Earth's appear to be promising targets for surface characterization by a future direct imaging mission.
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| 8. |
- Grady, Christine, et al.
(författare)
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Broad Consent for Research With Biological Samples : Workshop Conclusions
- 2015
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Ingår i: American Journal of Bioethics. - : Informa UK Limited. - 1526-5161 .- 1536-0075. ; 15:9, s. 34-42
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Tidskriftsartikel (refereegranskat)abstract
- Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Center's Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.
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| 9. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 10. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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